We will develop microminiaturized cell-culture environments, i.e., NanoLiter BioReactors (NBR) for growing and maintaining populations of I to 100 cultured mammalian cells in volumes three orders of magnitude smaller than in standard multi-well screening plates. This would reduce the time required for diffusive mixing, thermal equilibrium, and for cells to grow to confluence; simplify accurate cell counting; minimize required volumes of expensive pharmaceuticals or toxins; and allow thousands of culture chambers on a single instrumented chip. Our long-term goal is to develop a new class of miniature, automated cell-based bioanalyzer arrays for monitoring the immediate environment of multiple cell lines and assaying the effects of drug or toxin exposure. This proposal would develop a NBR that detects cellular responses, provides appropriate control signals, and makes closed-loop adjustments of the environment (in Phase II), e.g., by adjusting temperature, pH, ionic concentrations, or by applying another drug or a selective toxin antidote. To characterize in a nonspecific manner the metabolic activity of cells, the biosensor elements of the NBR will include an isothermal picocalorimeter to monitor heat response, and planar pH, dissolved oxygen and redox potential sensors. We will demonstrate short-term and long-term cultivation of several mammalian cell lines and monitor their response to test substances. The proposed technique will enable automated, parallel and multiphasic monitoring of multiple cell lines for drug and toxicology screening. PROPOSED COMMERCIAL APPLICATION: The unique capabilities of this technology would allow analysis of nonspecific responses to an unknown insult. It can lead to massively parallel screening of pharmaceuticals, toxins and other stresses. Once converted into a fully automated system and data analysis and data reduction algorithms are fully developed (in Phase II), this equipment could be readily commercialized, and sold to pharmaceutical companies, research laboratories, and environmental monitoring services.